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Updated: Apr 27, 2026
A Simple Bioassay for the Evaluation of Vascular Endothelial Growth Factors
Published on: March 15, 2016
Discovery of novel inhibitors of vascular endothelial growth factor-A-Neuropilin-1 interaction by structure-based
Anna Starzec1, Maria A Miteva2, Patrick Ladam3
1Université Paris 13, Sorbonne Paris Cité, EA4222, 74 rue Marcel Cachin, 93017 Bobigny cedex, France.
Abstract:
Neuropilin-1 (NRP-1), one of the most important co-receptors of vascular endothelial growth factor-A (VEGF-A), increases its angiogenic action in several chronic diseases including cancer by increasing the activity of associated tyrosine kinase receptors, VEGFR1 and VEGFR2. Binding of VEGF-A to NRP-1 plays a critical role in pathological angiogenesis and tumor progression. Today, targeting this interaction is a validated approach to fight against angiogenesis-dependent diseases. Only anti-NRP-1 antibodies, peptide and peptidomimetic drug-candidates or hits have been developed thus far. In order to identify potent orally active small organic molecules various experimental and in silico approaches can be used. Here we report, novel promising small drug-like molecules disrupting the binding of VEGF-A₁₆₅ to NRP-1. We carried out structure-based virtual screening experiments using the ChemBridge compound collection on the VEGF-A₁₆₅ binding pocket of NRP-1. After docking and two rounds of similarity search computations, we identified 4 compounds that inhibit the biotinylated VEGF-A₁₆₅ binding to recombinant NRP-1 with Ki of about 10 μM. These compounds contain a common chlorobenzyloxy alkyloxy halogenobenzyl amine scaffold that can serve as a base for further development of new NRP-1 inhibitors.
Insights
Researchers identified novel small molecules that disrupt the binding of vascular endothelial growth factor-A (VEGF-A) to Neuropilin-1 (NRP-1). This finding offers a new strategy for developing orally active drugs targeting angiogenesis in diseases like cancer.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Neuropilin-1 (NRP-1) acts as a co-receptor for vascular endothelial growth factor-A (VEGF-A), enhancing its pro-angiogenic activity.
- VEGF-A/NRP-1 interaction is crucial for pathological angiogenesis and tumor progression, making it a therapeutic target.
- Current therapeutic strategies primarily involve antibodies, peptides, and peptidomimetics, with a need for orally active small molecules.
Purpose of the Study:
- To identify novel, orally active small organic molecules that disrupt the VEGF-A₁₆₅ and NRP-1 binding interaction.
- To establish a foundation for developing new NRP-1 inhibitors for anti-angiogenesis therapies.
Main Methods:
- Structure-based virtual screening of the ChemBridge compound collection against the NRP-1 binding pocket.
- Docking and similarity search computations to identify potential drug candidates.
- In vitro assays to confirm inhibition of biotinylated VEGF-A₁₆₅ binding to recombinant NRP-1.
Main Results:
- Identified four small drug-like molecules that inhibit VEGF-A₁₆₅ binding to NRP-1.
- The identified compounds demonstrated inhibition with a dissociation constant (Ki) of approximately 10 μM.
- A common scaffold, chlorobenzyloxy alkyloxy halogenobenzyl amine, was identified in the active compounds.
Conclusions:
- The identified small molecules represent promising leads for developing novel NRP-1 inhibitors.
- The discovered scaffold provides a basis for further optimization of drug-like properties and potency.
- This research opens avenues for orally administered therapeutics targeting angiogenesis-dependent diseases.
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